Diabetes mellitus, often referred to simply as diabetes, encompasses a variety of conditions due to abnormal energy metabolism, characterized by chronic high blood glucose levels (hyperglycemia). Blood glucose levels are controlled by a complex network of chemicals and hormones in the human body. Since glucose is the main body fuel, there are many stress hormones which maintain blood glucose within a narrow range of 4-8 mmol/l by converting energy store (fat and glycogen) to glucose. On the other hand, insulin, produced by the beta cells of the pancreas, is the only hormone which can reduce blood glucose by promoting glucose uptake in the peripheral tissues. Thus, the abnormally high level of blood glucose in a person with diabetes is caused by defects in either insulin secretion or insulin action, attributable to a combination of hereditary, acquired, and environmental factors. Majority of diabetes are either type 1 diabetes, previously known as childhood-onset diabetes or insulin-dependent diabetes, or type 2 diabetes, previously known as adult-onset diabetes or non-insulin-independent diabetes.
Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, resulting in a deficiency of insulin production. The principal treatment for this type of diabetes is therefore delivery of artificial insulin, usually via injection. Type 2 diabetes (T2D) is more common than type 1 diabetes with over 90% of affected people having T2D. The latter is closely associated with modernization characterized by obesity and insulin resistance (reduced sensitivity to insulin action) although diminished insulin production is needed for development of overt hyperglycemia. Both twin and family studies support a strong genetic component for T2D. Recent genome wide association studies implicate multiple common genetic variants in the development of T2D although these factors only explained a small percentage of the variance of the genetic risk of T2D. Many of these variants are located in non-coding regions, suggesting that dysregulation of gene expression may play a pivotal role in complex diseases such as diabetes. Furthermore, there is strong evidence showing inter-ethnic differences in distribution and frequency of genetic or sequence variants for diabetes such that many of these variants discovered in Caucasian populations may not be applicable to Asian population. Apart from different developmental, environmental and cultural factors which can initiate, perpetuate and modify the clinical course, genomic architectural variations such as patterns of linkage disequilibrium (LD), recombination hotspots, insertion/deletion and copy number variations, DNA sensitive sites, regulatory regions for epigenetic phenomenon and fetal programming may all contribute to these inter-ethnic differences. See, e.g., Chan et al., JAMA, 2009. 301(20): p. 2129-40; Ramachandran et al., Lancet, 2010. 375(9712): p. 408-18.
Various factors are known to be indicative of a person's risk to develop T2D, most of them strongly influenced by the person's lifestyle, age, ethnic background, and family history. The presence of at least one, often more than one, of these risk factors, such as a body mass index (BMI) in the range of obesity (especially central obesity due to accumulation of excess visceral fat as indicated by large waist circumference), elevated blood glucose or insulin level (especially elevated fasting or post prandial blood glucose or insulin level), and reduced sensitivity to insulin, predisposes a person to the high likelihood of developing T2D, if no corrective measure is taken.
As people's living standards continue to improve globally, the number of individuals suffering from diabetes is also rapidly increasing. The World Health Organization (WHO) estimates that by 2030 the number of people living with diabetes will exceed 350 million worldwide. Due to the rising incidence of diabetes, its chronic nature without an ultimate cure, and serious health implications associated with its complications, including but not limited to cardiovascular disease, kidney failure, cancer, blindness, leg amputation, there exists an urgent need for new and effective means to assess or predict the risk of individuals who might later develop diabetic conditions, so that prophylactic measures can be taken to prevent or delay the onset of diabetes in these individuals or to reduce severity of the pertinent symptoms/risks associated with diabetes.
There are also clinical and experimental data showing that good glycemic control and use of certain drugs such as statins (which inhibit the HMG coA reductase), blockers of renin angiotensin system, and blood glucose lowering drugs including but not limited to insulin, sulphonylureas, metformin and glitazones, may reduce the risk of not only cardiovascular and renal diseases but also cancer (see, e.g., Yang et al., Diabetes, Obesity and Metabolism 2012 14:579-85; and Yang et al., Diabetes Metab Res Rev 2012; 28:379-87). These preventive measures are especially important in high risk subjects such as those who have additional risk factors for cardiovascular disease, e.g., positive family history of diabetes (suggesting the possibility of harboring other (epi)genetic factors yet to be identified), chronic kidney disease, chronic infection (e.g., hepatitis B and C) and a combination of low BMI (reflecting poor pancreatic beta cell reserve) and high waist circumference (reflecting increased visceral fat with insulin resistance) In these high risk subjects, detection of genetic risk factors before severe metabolic decompensation will help clinicians to intensify treatment in order to prevent metabolic deterioration and optimize metabolic control to reduce risk of cancer, cardiovascular and renal disease.
Because of the enormous social and economical impact the above discussed diseases impart globally, there exist clear and immediate needs to develop new and effective means for accurate diagnosis of these diseases or early assessment a patient's risk of developing these diseases in the future, such that early intervention may be performed to minimize the harmful effects associated with these diseases and/or the risk of developing the diseases. The present invention fulfills this and other related needs.